Our goal is to understand the molecular mechanisms of the physiological and pathological effects of hemodynamic flow. Over the last decade, we have investigated the signaling pathways by which human endothelial sense and respond to various regimes of shear stress. We are now in the position to propose a molecular model of mechanoreception and mechanochemical transduction in human endothelial cells. Fluid flow stimulates numerous response in endothelial cells. These include production of vasoactive factors and growth factors. Intracellularly, several signal transduction pathways are triggered. Many of these responses are mediated by G protein activation. Here, we propose that the fluid shear stress acts on the endothelial cell membrane, and by altering membrane fluidity activates the G protein Gq and Gi3, and particularly nitric oxide synthase. The objective is to test the overall hypothesis that the plasma membrane is the mechanoreceptor for shear stress and membrane-associated nitric oxide synthase and G proteins are the mechanochemical transducers. We will test this hypothesis by variety of cellular, biochemical, molecular and biophysical methods. In particular, we will investigate if the mechanoreceptor and mechanotransducers are the ones we have proposed by genetically knocking out the candidate the G proteins. In addition, we will determine the membrane domains where the mechanotransducing proteins are located using spectroscopic techniques. We believe that this investigation will provide fundamental understanding of how the endothelium senses hemodynamic forces in normal physiology and in vascular disease. In addition, it will provide a rational basis for treated vascular disease processes.